Severe deficiencies and abnormalities in rat cerebellar DNA synthesis have been found in the conditions of hyperthyroidism, hypothyroidism, and hyperglucocorticism. The purpose of this project is to study the effects of thyroid and adrenal hormones upon key enzymes critical to the incorporation of pyrimidines into DNA in developing rat brain. DNA synthesis requires incorporation of pyrimidine nucleotides via the de novo pyrimidine biosynthetic pathway using the simple substrates HCO3, ATP and glutamine, and by a salvage pathway in which preformed pyrimidine nucleosides are phosphorylated by kinase enzymes. It is our hypothesis that the activities of the first two enzymes of the de novo pyrimidine pathway, carbamyl phosphate synthetase and aspartate transcarbamylase, and activities of two salvage pathway enzymes, thymidine kinase and uridine kinase, in the developing cerebellum are dependent in some manner on the thyroid and adrenal glucocorticoid hormones. The rat cerebellum will be used in this study because of its extraordinary increase in DNA (cell number) in the first 3 postnatal weeks and its ready accessibility for dissection and biochemical study. To test this hypothesis, experiments have been designed to compare the developmental curves of each of the four enzymes in normal cerebella with curves established from animals rendered hyperthyroid, hypothyroid, and hyperglucocorticoid. The experiments are contructed separately for each endocrinopathy and will be accompanied by parallel studies of developmental histopathology and concomitant studies of developmental behavior which will be used to discriminate parameters of behavior which are sequellae of the morphological and biochemical disturbances. Results from these experiments will provide data which should lead to a better understanding of the relationships between hormones, enzyme systems during development, and the behavioral outcomes. The elucidation of such relationships may serve to clarify the biochemical pathology underlying the brain damage in human neonatal hypothyroidism and provide data for further understanding of the biochemical effects upon the nervous system of exogenous corticosteroid administration in the human infant.